CN110354248A - Application of the peptidomimetic aldehyde compound in preparation treatment swine fever virus (ASFV) infectious disease drug - Google Patents
Application of the peptidomimetic aldehyde compound in preparation treatment swine fever virus (ASFV) infectious disease drug Download PDFInfo
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Abstract
The present invention relates to peptidomimetic aldehyde compound I, application of the compound II in preparation treatment swine fever virus (ASFV) infectious disease drug, its various optical isomer, pharmaceutically acceptable solvate and prodrug are further related in the application of preparation treatment swine fever virus (ASFV) infectious disease drug.The invention further relates to Formulas I is contained, the pharmaceutical composition of Formula II structure peptidomimetic aldehyde compound treats the application of swine fever virus (ASFV) infectious disease drug in preparation.I
Description
Technical field
The present invention relates to compound, pharmaceutical composition and this kind of compounds for the treatment of infection swine fever virus (ASFV)
Synthetic method, formulation method.Specifically, the present invention provides two peptidomimetic aldehyde compounds, the drug containing this kind of compound
Composition and the method for this compounds for treating swine fever virus (ASFV) infection.
Background technique
African swine fever (African swine fever, ASF) is a kind of acute, hemorrhagic, strong pig transmissible disease
Disease is caused by African swine fever virus (African swine fever virus, ASFV), and lethality reaches as high as 100%.ASF
It is characterized in that disease time is short, infects fastly, clinical manifestation is high fever (40-42 DEG C), rapid heart beat, expiratory dyspnea, the positions such as eye nose
Have serosity or a mucopus sexual secretion, skin cyanosis, lymph node, gastrointestinal mucosa has obvious bleeding.ASF is that the world is dynamic
The specified statutory report animal epidemics of object health organization (OIE), the same disease are also a kind of animal epidemic disease of China's guard key
Feelings.
In the 1920s, the swine fever disease as caused by ASFV confirms in Kenya for the first time.In the 1950s, ASF
It is broken out in Europe, and then propagates to South America and Caribbean area.2007, the disease was again in Caucasus region prevalence, especially
It is Georgia.2014, ASF appeared in eastern Europe, then in Russian eruption and prevalence.2018 China Nian8Yue Fen report
First case ASF case is accused, until whole nation today has multiple province outburst ASF.China has added up to slaughter live pig 600,000, the disease
Disease has brought tremendous economic losses to China raiser.
ASFV is the pathogen for causing ASF, belong to African swine fever virus section (AsfarviridaeIt family), is a kind of
The coated double-stranded DNA virus of cyst membrane.Regular dodecahedron is presented in virion, and particle diameter is in 200 nm or so.ASFV molecule knot
Structure is complicated, and in terms of different separating resultings, between 170 kb-190 kb, shared about 151-167 are opened viral genome
Putting property reading frame.ASFV encodes assembling of many albumen for virion, the duplication of auxiliary gene group and reparation, and for resisting
The immunization of host.Viral genome is wrapped up by thick lining protein mass shell, and outer is inner membrance.It is positive 20 except inner membrance
The coat protein layer of face body, and be coated with by outer membrane.
ASFV infects the monocyte and macrophage of pig, and virus passes through clathrin-mediated endocytosis effect or pinocytosis
Effect intrusion cell.Virion is after invading cell, as protein shell depolymerisation occurs for the induction of acid condition, thus
Inner membrance is promoted to merge with late endosomal film, releasing virus core to cytoplasm.Viral genome transcribes pole early stage and early stage first
Gene carries out the duplication of genome, transcription under the protein regulation of these genes coding.Due to answering for African swine fever virus structure
Polygamy has identified the albumen come at present and there was only 68 kinds, only accounted for the 39% of its genome encoding ability.
Although having identified the composition that part albumen participates in African swine fever virus at present, for its structural proteins and
The research of functional protein is thorough not enough, does not go deep into the research of important target proteins structure and function, this also counteracts non-
The exploitation of continent classical swine fever virus vaccine and inhibitor.
Laboratory stage is also rested at present for the vaccine research of African swine fever virus, it was reported that by African swine fever virus
One or two of live virus genome clpp gene, which is removed, to be prepared into attenuated live vaccine and can induce protection activity, also
Other vaccines such as DNA vaccination researched and developed etc., may become vaccine candidate object, but distance put goods on the market it is far away.?
Before obtaining effective vaccine, developing effective inhibitor is also an important measures to viral infection resisting, and antiviral drugs is wide
General to be applied to human infection, zoonosis is using less.Developing effective antiviral drugs can be used for after Epidemic outbreak of disease early
Phase controls viral transmission, can also be applied to drug and is combined with vaccine inoculation to cause the expansion that immune response effectively prevent swine fever virus
It dissipates.
Many viruses would generally encode protease during duplication and carry out the processed of polyprotein or precursor protein
The effects of journey, performance controls the expression, assembling and maturation of virus protein.Such as positive chain RNA virus and retrovirus encode
Polyprotein is cut through virus protease proteolysis, generates its duplication and required non-structural protein and structure occur for form
Albumen.DNA virus, if adenovirus and poxvirus usually synthesize precursor protein, precursor protein removes end by protease hydrolytic
Small peptide could be mature.It is weighed very much in conclusion virus protease has played during the maturation of virus protein and assembling
The effect wanted is related to the effective duplication and existence of virus.
African swine fever virus protease S273R is the cysteine proteinase of a 31kDa, belongs to SUMO-1 specific protein
White enzyme family, with the SUMO-1 protease identification sequence GG-X having the same in eukaryocyte.African swine fever virus is being replicated
It is pp220 and pp62 that process, which synthesizes 2 polyproteins, the two polyproteins generate under the hydrolysis of protease pS273R
6 kinds of structural proteins, this 6 kinds of structural proteins account for about the 30% of entire mature virion proteins amount, constitute virus nucleocapsid
Main component.Wherein pp220 is produced mature virus structural protein p150, p37 after protease pS273R hydrolysis, p14,
P34, pp62 are produced mature virus structural protein p35 and p15 after being hydrolyzed by protease pS273R, this 6 kinds of structural proteins and
Protease pS273R is positioned at the nucleocapsid region of virus, is connected to the kernel containing DNA genome and internal coating,
Very important effect has been played in the assembling process of African swine fever virus.
Research shows that African swine fever virus can also utilize precursor polyprotein in the case where lacking protease S273R
Pp220 and pp62 are assembled, but assembling the virus come does not have infection duplication ability.In conjunction with the research of albuminoid enzyme,
It was found that the adenovirus protease AVP for belonging to SUMO-1 specific proteins enzyme family is the shell mistake of undressing due to having blocked adenovirus
Journey causes adenovirus to lose infection ability.Therefore, it is presumed that African swine fever virus is when lacking protease S273R effect,
Due to having blocked the shell process of undressing of African swine fever virus particle, lead to the forfeiture of infection ability.
In conclusion the hydrolysis processing program of protease is in the morphogenetic process of African swine fever virus with important
Adjustment effect.Therefore, protease S273R can be used as the exploitation that drug target carries out inhibitor.
Currently, the outburst of China African swine fever virus is serious, had brought tremendous economic losses to China.Therefore, conjunction is utilized
The drug that the development costs of reason develop anti-African swine fever virus is extremely urgent.Our invention is with S273R protease
As drug target, the higher inhibitor of activity is developed.
Summary of the invention
The present invention relates to Formulas I, the peptidomimetic aldehyde compound of II and/or pharmaceutically acceptable hydrate preparation treatment pig
The application of pestivirus (ASFV) infectious disease drug.These compounds are as its pharmaceutically acceptable hydrate or conduct
Pharmaceutical composition ingredient (whether is it the antivirotic with other treatment African swine fever disease, anti-infectious agent, immunomodulator or
Antibiotic is administered simultaneously) and be used to inhibit the S273 protease of ASFV virus or the one or more ASFV viruses of preventing/treating
Infection symptoms.
More particularly, it relates to Formulas I, II compound and/or the preparation treatment of pharmaceutically acceptable hydrate
The application of swine fever virus (ASFV) infectious disease drug:
Formulas I
Formula II
The pharmaceutical composition for including in the scope of the invention, Formulas I or Formula II compound comprising anti-ASFV anti-viral effective amount or its control
Acceptable salt in treatment, with pharmaceutically acceptable pharmaceutical carrier or auxiliary agent.
An importance of the invention is related in mammals, by giving effective anti-ASFV to the mammal
The compound of formula I or Formula II compound or its acceptable salt or ester or above-mentioned composition in the treatment of the content of virus, with
The method for treating swine fever virus (ASFV) infectious disease drug.
Another importance of the invention, be related to by make virus be exposed to inhibit ASFV virus I Formula II or its
Acceptable salt or ester in treatment find the active drug for the treatment of African swine fever disease as under above-mentioned composition.
The pharmaceutical composition that other aspects are related to, can also comprise other anti-ASFV preparations, may also include ASFV virus
Other targets inhibitor, such as transmethylase, dUTP enzyme etc..
The detailed description of preferred embodiment
Definition:
As described herein, unless separately referring to, it is applicable in following definition:
About example, (R) or (S) is used to indicate the absolute configuration of asymmetric center, and it is saying for entire compound that this, which is indicated,
Bright rather than individually substituent group explanation.
Preferred scheme
The compound of the present invention can form hydrate or solvate.It is known to those skilled in the art to freeze compound together with water
Hydrate or the in the solution method with formation solvate when the concentration of suitable organic solvent are formed by when dry.
The present invention includes the drug containing therapeutic dose the compounds of this invention and one or more pharmaceutically acceptable carriers
And/or the pharmaceutical composition of excipient.Carrier includes such as salt water, buffered saline, glucose, water, glycerol, the knot of ethyl alcohol and they
Close object.Carrier or excipient can also include time delay material known in the art, such as glycerin monostearate or distearyl
Acid glyceride may also include wax, ethyl cellulose, hydroxypropyl methyl cellulose, methylmethacrylate etc..If desired, should
Composition can also include small amount of wetting agent or emulsifier or pH buffer.The composition can be liquid, suspension,
Emulsion, tablet, pill, capsule, extended release preparation or powder.The composition can use traditional such as three acid of binder and carrier
Glycerides are at suppository.Oral preparation may include the mannitol of standard vector such as drug grade, lactose, starch, tristearin
Sour magnesium, saccharin sodium, cellulose and magnesium carbonate etc..Optionally depending on preparation, preparation can design mixing, granulation and compression or molten
Solve ingredient.In another approach, the composition can be configured to nano particle.
Pharmaceutical composition of the invention can be administered with miscellaneous medicament forms.The pharmaceutical carrier used can be solid
Body or liquid.
If preparation can be tablet, the powder being placed into hard capsule or piller form or ingot using solid carrier
Agent or Lozenge forms.The amount of solid carrier largely changes, it is preferred that from about 25mg to about 1.0g.Typical solid
Carrier includes lactose, land plaster, sucrose, talcum, gel, agar, pectin, Arabic gum, magnesium stearate, stearic acid etc..Gu
Body carrier may include it is one or more may be used as fumet simultaneously, lubricant, solubilizer, suspending agent, filler, glidant,
The substance of compression aid, adhesive or tablet-disintegrating agents；It may also is that encapsulating material.In the powder, carrier is fine crushing
Solid, the mixing of the active constituent of it and fine crushing.Active constituent and the load with necessary compression property in tablets
Body mixes in proper proportions, is compressed with the shapes and sizes of needs.Powder and tablet preferably comprise at most 99% active constituent.
If preparation can be syrup, emulsion, soft capsule, in ampoule or bottle or non-aqueous liquid using liquid-carrier
Aseptic injectable solution or suspension in suspension.Typical liquid-carrier includes syrup, peanut oil, olive oil, water, etc..
Liquid-carrier is used to prepare solution, suspension, emulsion, syrup, the composition of tincture and sealing.Active constituent can be dissolved or be hanged
Float on pharmaceutically acceptable liquid-carrier such as water, organic solvent, the mixture of the two or pharmaceutically acceptable oils or rouge
Fat.Liquid-carrier may include other suitable medicated premix such as solubilizer, emulsifier, buffer, preservative, sweetener,
Fumet, suspending agent, thickener, pigment, viscosity modifier, stabilization form osmo-regulators.It is given for oral and parenteral
The suitable example of the liquid-carrier of medicine includes that water is (excellent partly comprising such as above-mentioned additive, such as cellulose derivative
Select sanlose solution), alcohol (including monohydric alcohol and polyalcohol, such as ethylene glycol) and their derivative, and oil
Class (such as fractionated coconut oil and peanut oil).Carrier for parenteral administration can also be grease such as ethyl oleate and isopropyl
Myristate.Sterile liquid-carrier is used for the sterile fluid composition of parenteral administration.Liquid for pressurized compositions
Body carrier can be halogenated hydrocarbons or other pharmaceutically acceptable propellants.Sterile solution or aaerosol solution composition of liquid medicine
It can be used to, for example, intravenously, it is intramuscular, in peritonaeum or it is subcutaneously injected.Can be according to the known technology of this field, use is appropriate
Dispersing agent or wetting agent (such as Tween 80) and suspending agent deploy the suspension.Single push-in or 30 points can be gradually injected when injection
Perfusion in the passages through which vital energy circulates of clock.The compound can also be administered orally in the form of liquid or solid composite.It is used herein
In one word of parenteral, including subcutaneous, intradermal, intramuscular, intravenous, intra-articular, intrasynovial, breastbone, intrathecal and intralesional injection
Or infusion techn.
In order to obtain stable water-soluble dosage form, compound can be dissolved in the aqueous solution of organic or inorganic acid, 0.3M
Succinic acid or citric acid solution.If cannot get soluble form, compound can be dissolved in suitable cosolvent or their combination.
The example of such suitable cosolvent includes but are not limited to, and concentration range is from the ethyl alcohol of 0-60% total volume, and the third two
Alcohol, Liquid Macrogol, polysorbate 80, glycerol, polyoxyethylene fatty acid ester, fatty alcohol or glycerol hydroxy fatty acid ester etc..
Pharmaceutical composition of the invention is orally available, parenteral or is administered by the reservoir of implantation, oral administration or logical
It crosses preferred when drug administration by injection.Various release systems be it is known and can be used for compound or other various preparations to
Medicine, these preparations include tablet, capsule, the solution of injectable, the capsule in liposome, particle, microcapsules, etc..It introduces
Method includes but is not limited to skin, intradermal, intramuscular, intravenous in peritonaeum, subcutaneous, in nasal cavity, lung,
It is peridural, eyes and (generally preferable) oral route.Compound can be by any convenient or other appropriate
Approach administration, such as by injection or bolus injection, by epithelium or mucous membrane route (for example, oral mucosa, rectum and intestines are viscous
Film, etc.) it absorbs or can be administered by the bracket of carrying medicament and together in other biological activities agent.It can be with whole body or office
Portion's administration.For nose, when the treatment or prevention of bronchus or lung disease, preferred administration route is oral, nasal administration or branch gas
Pipe smoke agent or sprayer.
Being familiar with this field, this will be understood that and may need than higher or lower dosage mentioned above.To the spy of particular patient
Determine dosage and processing mode should be according to various factors depending on, the activity including used specific compound, the age of patient,
Weight, gender, general health status, diet, the combination of the time of administration, metabolic rate, drug, and infection seriousness and
Process, patient are to the tendency of infection, and there are also the judgements for handling doctor.In general, to be substantially below the best of the compound
The low dose of dosage starts to treat.Then lead to too small amount of increase and increase dosage, until reaching optimal effect in this case
Until fruit.In general, it is desirable that be typically enough to generate effective antiviral as a result, but not causing any harmful or unfavorable pair
The levels of effect administer the compound.
When composition of the invention include formula (I) compound or formula (II) compound and one or more other treatments or
When prophylactic combines, the amount of the compound and other preparation should be provided with the dosage level between about 10 to 100%,
More preferably from about 10 to 80% dosage is usually given with single therapy method.
When these compounds are deployed together with pharmaceutically acceptable carrier, resulting composition is in vivo given
Mammal, such as mankind are given, to treat or prevent ASFV virus infection.It can also be used the compounds of this invention and lower series preparation mixed
It closes, to complete this kind for the treatment of, including but not limited to: immunomodulator, such as α, β, δ-interferon；Other anti-virus formulations,
Such as acyclovir, Ganciclovir；Inhibitor of the others for the S273R protease of ASFV；To ASFV life circulation in its
The inhibitor of his target, such as transmethylase, dUTP enzyme etc. or combinations thereof object.Other preparation can be mixed with the compounds of this invention
It closes, to generate single dosage form.In addition, mammal can also be administered this kind of other preparation respectively, become multiple
A part of dosage form.Therefore, the other concrete schemes of the present invention provide one kind in mammals, by giving formula (I)
(II) compound inhibits the method for ASFV virus.
In preferred concrete scheme, these methods have in mammals for reducing ASFV replication capacity.If medicine
Compositions only include the compounds of this invention as active constituent, and such methods can be also comprised to give the mammal and be selected
From immunomodulator, antivirotic, inhibitor of the others for the S273R protease of ASFV；To in ASFV life circulation
The step of inhibitor of other targets, such as transmethylase, dUTP enzyme etc. or combinations thereof object.Can give the present composition it
Before, simultaneously or after, give this kind of other preparation to mammal.
Process flow:
The compounds of this invention I, II are synthesized according to the ordinary procedure illustrated in process I.
Process I:
The compounds of this invention I, II synthesize to obtain through the route of process I, in the process, using Pidolidone as starting material,
By raw material carboxyl ester under the conditions of existing for the thionyl chloride, then existing for the triethylamine under the conditions of will be former with Boc acid anhydrides
The amino of material carries out protection synthetic intermediate 2, and under the conditions of existing for the LIHMDS, intermediate 2 is reacted with bromoacetonitrile, makes its transformation
For intermediate 3.Under the conditions of then existing for the cobalt chloride, intermediate 3 is intermediate 4 by sodium borohydride reduction.Intermediate 4 passes through
Three step condensation reactions, synthesize intermediate 7.With rear center body 7 by sodium borohydride reduction be intermediate 8.8 quilt of last intermediate
Dess-Martin reagent oxidation is final product I and II.
By taking R is ethyl as an example, the synthesis process of process I is sketched.In ordinary procedure, wherein R expression be ethyl or
Benzyl.
(a) (1) SOCl2, MeOH, Reflux, 2h; (2) (Boc)2O, TEA, anhydrous THF; (b) (1)
LiHMDS, anhydrous THF; -78oC; (2) BrCH2CN, anhydrous THF, -78oC; (c) CoCl2·
6H2O, NaBH4, MeOH, 0oC; (d) (1) TFA, DCM, RT, 3h; (2) change pH to 7, Boc-L-
Leu-OH, EDCI, HOBt and TEA, DCM;(e) (1) TFA, DCM, RT, 3h; (2) change pH to 7,
Boc-L-Abu-OH or Boc-L-Phe-OH, EDCI, HOBt and TEA, DCM; (f) (1) TFA, DCM, RT,
3h; (2) cinnamic acid , EDCI, HOBt and TEA, DCM; (g) NaBH4, MeOH, RT, 2h; (h)
DMP, DCM, RT, 1 h,
The preparation of step a. compound 2: Pidolidone (10.0 g, 67.97 mmol) is dissolved in 200 mL methanol, is delayed under ice bath
It is slow that SOCl is added dropwise2(10.85 mL, 149.53 mmol), finish, and after 65 °C are flowed back 2 hours, are cooled to room to reaction system
Temperature, evaporated under reduced pressure methanol obtain colorless viscous shape substance.The colorless viscous shape substance is dissolved in 200 mL THF, under ice bath,
It is added (Boc)2O(22.25 g, 101.95 mmol), then triethylamine (14.13 mL, 101.95mmol) are slowly added dropwise.Add
Finish, room temperature reaction is overnight.After completion of the reaction, evaporating solvent under reduced pressure.Residue is dissolved in 200 mL methylene chloride.Successively use water
(200 mL*2), saturated citric acid solution (200 mL*2), saturated sodium bicarbonate solution (200 mL*2) and saturated salt solution
(200 mL*2) washs organic phase.Organic phase anhydrous Na2SO4It dries, filters and collects filtrate, evaporating solvent under reduced pressure, residue column
Chromatographic purifying (petroleum ether: ethyl acetate=4:1 v/v) obtains colorless oil as product 2(18.34g, yield 98%)
The preparation of step b. compound 3: compound 2(10.0 g, 36.4 mmol) it is dissolved in the dry THF of 200 mL, -78 °C
Under nitrogen protection, be slowly added dropwise hexamethyldisilazide lithium (LiHDMS) THF solution (80.0 mL, 1 mol/L, 80
Mmol), finish, reacted 1 hour under -78 °C.2- bromoacetonitrile (6.55 g, 54.6 mmol) are slowly added dropwise again, finish, -78 °C
Lower reaction 1.5 hours.After completion of the reaction, it sequentially adds the methanol (30 mL) pre-cooled and glacial acetic acid (30 mL) is quenched instead
It answers.Reaction system is moved to room temperature to continue to stir, when system is warmed to room temperature, evaporating solvent under reduced pressure.Gained residue is dissolved in
In 100 mL of methylene chloride, organic phase is washed with saturated salt solution (200 mL*2).Organic phase anhydrous Na2SO4It dries, filters
Filtrate, evaporating solvent under reduced pressure are collected, residue column chromatographic purifying (petroleum ether: ethyl acetate=4:1 v/v) obtains faint yellow oil
Shape product 3(5.93 g, 18.9 mmol, 51.9%)
The preparation of step c. compound 4: compound 3(4.30 g, 13.68 mmol) it is dissolved in 100 mL anhydrous methanols, ice bath
Lower addition CoCl2·6H2O(1.96 g, 8.21 mmol), then NaBH is slowly added portionwise4 (3.12 g, 82.08 mmol).
It finishes, reacts at room temperature 12 hours.After completion of the reaction, 30 mL saturated ammonium chloride solution quenching reactions are added.Filtering is collected organic
Phase, evaporating solvent under reduced pressure are extracted with methylene chloride (50 mL*3), collect organic phase.It is washed with saturated salt solution (100 mL*2)
Organic phase.Organic phase anhydrous Na2SO4It dries, filters and collects filtrate, evaporating solvent under reduced pressure, residue column chromatographic purifying (petroleum
Ether: ethyl acetate=1:2 v/v) obtain faint yellow oil product 4(6.33 g, yield 55%).
The preparation of step d. compound 5: compound 4(1.9 g, 6.7 mmol) it is dissolved in anhydrous methylene chloride, ice bath
Under, CF is slowly added dropwise3COOH(5.0 mL, 67 mmol).It finishes, reacts at room temperature 3 hours.After completion of the reaction, it removes under reduced pressure molten
Agent, residue is dissolved in 30 mL methylene chloride, and under ice bath, reaction system is adjusted to about 7.0. and sequentially added by dropwise addition triethylamine
Boc-L-Leu-OH(1.53g, 6.7 mmol), EDCI(1.53 g, 8.0 mmol) and HOBt(1.08 g, 8.0
Mmol), triethylamine (3.8 mL, 26.8 mmol) are finally slowly added dropwise.It finishes, room temperature reaction is overnight.After completion of the reaction, it reacts
Liquid is successively used water (80mL*2), saturated citric acid solution (80 mL*2), saturated sodium bicarbonate solution (80 mL*2) and saturation food
Salt water (80 mL*2) washing.Organic phase anhydrous Na2SO4It dries, filters and collects filtrate, evaporating solvent under reduced pressure, residue column layer
Analysis purifying (methylene chloride: methanol=50:1 v/v) obtains white foam product 5(1.64 g, yield 62%).
The preparation of step e. compound 6a: compound 5a(1.5 g, 3.75 mmol) it is dissolved in anhydrous methylene chloride, ice
Under bath, CF is slowly added dropwise3COOH(2.8 mL, 37.5 mmol).It finishes, reacts at room temperature 3 hours.After completion of the reaction, decompression is steamed
Except solvent, residue is dissolved in 50 mL methylene chloride, under ice bath, triethylamine is added dropwise, reaction system is adjusted to about 7.0, successively plus
Enter Boc-L-Abu-OH(763 mg, 3.75 mmol), EDCI(864 mg, 4.51 mmol) and HOBt(609 mg, 4.51
Mmol), triethylamine (2.08 mL, 15.02 mmol) are finally slowly added dropwise.It finishes, reacts at room temperature 3 hours.After completion of the reaction,
Reaction solution is successively used water (80 mL*2), saturated citric acid solution (80 mL*2), saturated sodium bicarbonate solution (80 mL × 2) and
Saturated salt solution (80 mL*2) washing.Organic phase anhydrous Na2SO4It dries, filters and collects filtrate, evaporating solvent under reduced pressure, residual
Object column chromatographic purifying (methylene chloride: methanol=40:1 v/v) obtains white foam product 6a(1.33 g, yield 50%).
The preparation of step f. compound 7a: compound 6a(1 g, 2.06 mmol) it is dissolved in anhydrous methylene chloride, ice bath
Under, CF is slowly added dropwise3COOH(1.54 mL, 67 mmol).It finishes, reacts at room temperature 3 hours.After completion of the reaction, it removes under reduced pressure molten
Agent, residue is dissolved in 60 mL methylene chloride, and under ice bath, reaction system is adjusted to about 7.0. and sequentially adds meat by dropwise addition triethylamine
Cinnamic acid (306 mg, 2.06 mmol), EDCI(475 mg, 2.48 mmol) and HOBt(335 mg, 2.48 mmol), most
After triethylamine (1.14 mL, 8.25 mmol) are slowly added dropwise.It finishes, room temperature reaction is overnight.After completion of the reaction, reaction solution is successively
With water (80 mL*2), saturated citric acid solution (80 mL*2), saturated sodium bicarbonate solution (80 mL*2) and saturated salt solution
(80 mL*2) washing.Organic phase anhydrous Na2SO4It dries, filters and collects filtrate, evaporating solvent under reduced pressure, residue column chromatographs pure
Change (methylene chloride: methanol=30:1 v/v) and obtain faint yellow oil product 7a(574 mg, yield 46%).
The preparation of step g. compound 8a: compound 7a(500 mg, 0.97 mmol) it is dissolved in 40.0 mL anhydrous methanols
In, under ice bath, NaBH is added portionwise4(368 mg, 9.7 mmol).It finishes, reacts at room temperature 2 hours.After completion of the reaction, it is added
20 mL saturated ammonium chloride solution quenching reactions.Evaporating solvent under reduced pressure is extracted with ethyl acetate, and collects organic phase.Use saturated common salt
Water (30 mL × 2) washs organic phase.Organic phase anhydrous Na2SO4It dries, filters and collects filtrate, evaporating solvent under reduced pressure, residue
Column chromatographic purifying (methylene chloride: methanol=20:1 v/v) obtains white solid product 8a(400 mg, yield 75%).
The preparation of step h. final product compound I: compound 8a(300 mg, 0.62 mmol) it is suspended in 50.0 mL
In methylene chloride, ultrasound is partly dissolved it, under ice bath, be added portionwise Dess-Martin reagent (392 mg, 0.92
Mmol).It finishes, reacts at room temperature 1 hour.After completion of the reaction, 10 mL saturated sodium bicarbonate solutions are separately added into and 10 mL are thio
Metabisulfite solution quenching reaction.Reaction solution washs organic phase with saturated salt solution (30 mL*2).Organic phase anhydrous Na2SO4It is dry
It is dry, filtrate, evaporating solvent under reduced pressure is collected by filtration, residue column chromatographic purifying (methylene chloride: methanol=35:1 v/v) obtains white
Color solid product 1(230 mg, 77%)
Example
By following unrestricted example, the present invention is described in more detail, but the present invention is not limited to following instance.
Temperature is provided with centigrade.Unless separately state, Solution percentages indicate weight to the relationship of volume, and solution
The relationship of ratio expression volume-for-volume.Nuclear magnetic resonance (NMR) wide spectrum is recorded on the spectrometer of Bruker300MHz；With million
/ mono- (ppm) states chemical shift (δ), and the deuterated reagent with reference to inside.
Abbreviation used in embodiment includes Boc: tertbutyloxycarbonyl；L-Boc-Leu-OH: tertbutyloxycarbonyl protection
L-Leu；L-Boc-Abu-OH: the L- methylalanine of tertbutyloxycarbonyl protection；L-Boc-Phe-OH: tertbutyloxycarbonyl
The L-phenylalanine of protection；EDCI:1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride；HOBt:1- hydroxy benzo
Triazole；TFA: trifluoroacetic acid；DCM: methylene chloride；THF: tetrahydrofuran；DMSO: dimethyl sulfoxide；TEA: triethylamine；Et: second
Base；EtOAc: ethyl acetate；Me: methyl；MeOH: methanol；PE: petroleum ether；PBS solution: phosphate buffer；ESMS: electricity
Electrospray mass spectrometry analysis；MS: mass spectral analysis；HPLC: high performance liquid chromatography.
Embodiment 1. synthesizes (2R, 3S, 4R) -1- O- methyl -2- ketone -3- (2,4- dichloro-benzyloxy) -4- (2,4- dichloros
Benzyloxymethyl) tetrahydrofuran (1-5).
Formula (I)
It synthesizes to obtain compound I, white solid according to the step of process I.ESI-MS m/z: 485.3 (M+H); 1H
NMR (400 MHz, CD3CN) δ 9.42 (s, 1H), 7.91 (d, J = 6.8 Hz, 1H), 7.59 (dd, J =
9.3, 3.5 Hz, 3H), 7.47 – 7.36 (m, 3H), 7.23 – 7.05 (m, 2H), 6.70 (d, J = 15.7
Hz, 1H), 6.24 (s, 1H), 4.35 (dd, J = 11.2, 6.4 Hz, 1H), 4.25 (dd, J = 13.3,
6.1 Hz, 1H), 4.21 – 4.15 (m, 1H), 3.24 – 3.11 (m, 2H), 2.44 – 2.35 (m, 1H),
2.28– 2.22 (m, 1H), 2.05 – 1.98 (m, 1H), 1.88– 1.81 (m, 1H), 1.80– 1.71 (m,
3H), 1.67– 1.58 (m, 3H), 0.96 (t, J = 7.4 Hz, 3H), 0.92 (d, J = 5.8 Hz, 3H),
0.87 (d, J = 5.8 Hz, 3H). 13C NMR (101 MHz, CD3CN) δ 200.98, 179.79, 173.57,
172.44, 167.13, 140.90, 135.56, 130.28, 129.46, 128.35, 121.60, 57.81, 56.29,
52.35, 40.64, 40.39, 38.26, 29.92, 28.40, 25.28, 25.09, 22.92, 21.16, 10.07.
Embodiment 2.
Synthesize (2R, 3S, 4R) -1- O- methyl -2- ketone -3- (2,4- dichloro-benzyloxy) -4- (2,4- dichloro benzyloxymethyl) tetrahydro
Furans (II).
Formula (II)
It synthesizes to obtain compound (II), white solid according to the step of process I.ESI-MSm/z: 481.2 (M+H); 1H
NMR (400 MHz, CDCl3) δ 9.38 (s, 1H), 8.18 (d, J = 6.0 Hz, 1H), 7.67 (d, J =
7.7 Hz, 1H), 7.49 (d, J = 15.6 Hz, 1H), 7.35 (dd, J = 11.6, 8.2 Hz, 2H), 7.23
(d, J = 3.7 Hz, 3H), 7.17 – 7.10 (m, 5H), 7.04 (d, J = 7.0 Hz, 1H), 6.85 (s,
1H), 6.40 (d, J = 15.6 Hz, 1H), 4.92 (dd, J = 14.1, 6.8 Hz, 1H), 4.61 – 4.48
(m, 1H), 4.34 – 4.26 (m, 1H), 3.28 – 3.06 (m, 3H), 3.00 (dd, J = 13.6, 7.1
Hz, 1H), 2.42 – 2.34 (m, 2H), 2.28 – 2.22 (m, 1H), 1.95 – 1.86 (m, 1H), 1.86
– 1.75 (m, 1H), 1.75 – 1.59 (m, 2H), 1.57 – 1.47 (m, 2H), 0.79 (t, J = 6.5
Hz, 6H).13C NMR (101 MHz, CDCl3) δ 198.99, 179.04, 172.18, 170.39, 165.07,
140.73, 135.49, 133.49, 128.85, 128.31, 127.79, 127.47, 126.88, 125.93,
119.01, 56.28, 53.52, 51.10, 40.49, 39.60, 37.07, 36.91, 28.91, 27.16, 23.74,
21.85, 20.87.
Detailed description of the invention
Attached drawing 1 illustrates: the purifying figure of African swine fever virus S273R protease, protease cross the liquid phase of protein purification system
Figure.
Attached drawing 2 illustrates: the SDS-Page glue figure for each component that protease is collected after protein purification system.
Attached drawing 3 illustrates: the characteristics of being cut based on African swine fever virus S273R protease for substrate, the band fluorescence mark designed
The sequence diagram of the peptide substrate of note, for the zymetology level activity of inhibitor detects.
Attached drawing 4 illustrates: inhibitory activity curve of the compound I for African swine fever virus S273R protease.
Attached drawing 5 illustrates: inhibitory activity curve of the compound II for African swine fever virus S273R protease.
Claims (2)
1. compound of formula I, application of the Formula II compound in preparation treatment swine fever virus (ASFV) infectious disease drug:
。
2. a kind of application of pharmaceutical composition in preparation treatment swine fever virus (ASFV) infectious disease drug, the pharmaceutical composition
Including a effective amount of compound of formula I or with compound of formula I pharmaceutically acceptable mounting medium or auxiliary agent, also include effective quantity
Formula II compound or with Formula II compound pharmaceutically acceptable mounting medium or auxiliary agent.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112704731A (en) * | 2021-01-13 | 2021-04-27 | 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） | Application and method of protease S273R for inhibiting cell apoptosis |
| CN113817041A (en) * | 2021-10-29 | 2021-12-21 | 中国科学院昆明动物研究所 | Tick beta-defensin and application thereof |
| CN115927460A (en) * | 2022-08-11 | 2023-04-07 | 绍兴君斐生物科技有限公司 | Recombinant vector for resisting African swine fever virus transgene, pig fibroblast line, construction method and application thereof |
| WO2023137876A1 (en) * | 2022-01-20 | 2023-07-27 | 广州谷森制药有限公司 | Method for preparing intermediate for synthesizing new deuterated cyano compound |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838523A (en) * | 2011-06-23 | 2012-12-26 | 南开大学 | Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof |
| CN103130710A (en) * | 2011-11-29 | 2013-06-05 | 南开大学 | Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof |
| CN103145608A (en) * | 2011-12-07 | 2013-06-12 | 南开大学 | Anti-enterovirus 71 (EV71) caprolactam compounds, and preparation method and application thereof |
| CN105412906A (en) * | 2014-09-02 | 2016-03-23 | 南开大学 | Application of nucleoside compounds in preparing medicine for treating enterovirus 71 (EV71)-infected diseases |
-
2019
- 2019-04-26 CN CN201910342036.0A patent/CN110354248A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102838523A (en) * | 2011-06-23 | 2012-12-26 | 南开大学 | Anti-enterovirus 71 (EV71) valerolactam compounds, preparation method and uses thereof |
| CN103130710A (en) * | 2011-11-29 | 2013-06-05 | 南开大学 | Anti-enterovirus 71 (EV 71) caprolactam aldehyde compound and preparation method and purpose thereof |
| CN103145608A (en) * | 2011-12-07 | 2013-06-12 | 南开大学 | Anti-enterovirus 71 (EV71) caprolactam compounds, and preparation method and application thereof |
| CN105412906A (en) * | 2014-09-02 | 2016-03-23 | 南开大学 | Application of nucleoside compounds in preparing medicine for treating enterovirus 71 (EV71)-infected diseases |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112704731A (en) * | 2021-01-13 | 2021-04-27 | 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） | Application and method of protease S273R for inhibiting cell apoptosis |
| CN112704731B (en) * | 2021-01-13 | 2023-08-25 | 中国农业科学院哈尔滨兽医研究所（中国动物卫生与流行病学中心哈尔滨分中心） | Application and method of protease S273R for inhibiting cell apoptosis |
| CN113817041A (en) * | 2021-10-29 | 2021-12-21 | 中国科学院昆明动物研究所 | Tick beta-defensin and application thereof |
| CN113817041B (en) * | 2021-10-29 | 2023-05-26 | 中国科学院昆明动物研究所 | Tick beta-defensin and application thereof |
| WO2023137876A1 (en) * | 2022-01-20 | 2023-07-27 | 广州谷森制药有限公司 | Method for preparing intermediate for synthesizing new deuterated cyano compound |
| CN115927460A (en) * | 2022-08-11 | 2023-04-07 | 绍兴君斐生物科技有限公司 | Recombinant vector for resisting African swine fever virus transgene, pig fibroblast line, construction method and application thereof |
| CN115927460B (en) * | 2022-08-11 | 2023-08-29 | 绍兴君斐生物科技有限公司 | Recombinant vector for resisting African swine fever virus transgene, swine fibroblast cell line, construction method and application thereof |
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